U.S. patent number 5,440,057 [Application Number 08/110,095] was granted by the patent office on 1995-08-08 for access to taxol analogs.
This patent grant is currently assigned to The Scripps Research Institute. Invention is credited to Rodney K. Guy, Philippe G. Nantermet, K. C. Nicolaou, Hiroaki Ueno.
United States Patent |
5,440,057 |
Nicolaou , et al. |
August 8, 1995 |
**Please see images for:
( Certificate of Correction ) ** |
Access to taxol analogs
Abstract
Transformations of taxol, baccatin III and of 10-deacetyl
baccatin III provide access to novel taxol analogs and key
intermediates thereto.
Inventors: |
Nicolaou; K. C. (La Jolla,
CA), Nantermet; Philippe G. (San Diego, CA), Guy; Rodney
K. (San Diego, CA), Ueno; Hiroaki (San Diego, CA) |
Assignee: |
The Scripps Research Institute
(La Jolla, CA)
|
Family
ID: |
22331207 |
Appl.
No.: |
08/110,095 |
Filed: |
August 20, 1993 |
Current U.S.
Class: |
549/511 |
Current CPC
Class: |
C07D
305/14 (20130101); C07D 493/08 (20130101) |
Current International
Class: |
C07D
305/14 (20060101); C07D 305/00 (20060101); C07D
493/00 (20060101); C07D 493/08 (20060101); C07D
305/14 () |
Field of
Search: |
;549/511,510 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Richter; Johann
Assistant Examiner: Peabody; John
Attorney, Agent or Firm: Lewis; Donald G.
Claims
What is claimed is:
1. A method for producing a taxol analog comprising the following
steps:
Step A: reacting key intermediate 4, represented by the following
formula: ##STR7## with phosgene to produce carbonate 5, represented
by the following formula: ##STR8## wherein OTES is O-triethylsilyl;
and then Step B: acylating the carbonate 5 of said Step A with G,
wherein G is selected from the group consisting of phenyllithium
and the following structures: ##STR9## to produce the taxol analog
represented by the following formula: ##STR10##
Description
FIELD OF THE INVENTION
The invention relates to taxol and to the synthesis of taxol
analogs. More particularly, the invention relates to processes and
key intermediates for synthesizing taxol analogs.
BACKGROUND
Taxol is a natural product with anti-cancer activity. Because
natural sources of taxol are limited, synthetic methods for
producing taxol have been developed, e.g., K. C. Nicolaou et al.,
J. Chem. Soc., Chem. Commun. 1992, 1117-1118, J. Chem. Soc., Chem.
Commun. 1992, 1118-1120, and J. Chem. Soc., Chem. Commun. 1993,
1024-1026. Several synthetic taxol analogs have also been developed
and have been found to have altered chemical and biological
activity as compared to natural taxol, e.g., K. C. Nicolaou et al.,
Nature, 1993, 364, 464-466. There is considerable interest in the
design and production of further taxol analogs. However, progress
with respect to the synthesis of such taxol analogs has been
blocked by a lack of information regarding certain key synthetic
methods and key intermediates essential for the production of a
wide range of taxol analogs.
What is needed is the identification of key synthetic methods and
key intermediates for producing taxol analogs having altered
activities.
SUMMARY
Novel transformations of taxol, baccatin III and of 10-deacetyl
baccatin III are disclosed. These transformations and key
intermediates provide access to novel taxol analogs.
DETAILED DESCRIPTION
We disclose herein degradative studies of the natural taxol
product. Our objectives are bipartite: we provide first hand
knowledge about the chemistry of those compounds arising late in
our synthetic plan (supra) and we also provide access to the
synthesis of derivatives which have not been previously explored.
##STR1##
Our initial goal was to produce a C1-C2 vicinal diol that could be
used to explore benzoylation of the C2 hydroxyl group, a process
that we considered crucial to the success of our synthetic
endeavors. Towards this end, reductive deesterification of taxol
(1) followed by selective silylation of the C7 hydroxyl group with
triethyl silyl chloride (TES-Cl) produced, as per literature
precedent (Nicolaou, supra N. F. Magri et al., Journal of Organic
Chemistry 1986: vol. 51, pages 3239-3242; and J. N. Denis et al.,
Journal of the American Chemical Society 1988: vol. 110, pages
5917-5919), 7-TES Baccatin III (2) (Scheme 1). All attempts to
selectively deprotect the C2 and C10 positions, including both
metal hydride reduction and basic hydrolysis, produced a mixture
containing completely deesterified materials and rearranged
products giving extremely low (15-30%) yields of the desired
compound 4, a result which is in accordance with other groups
result's. We hypothesized that oxidation of the C13 hydroxyl group
would remove a suspected hydrogen bond between this hydroxyl group
and the C4 acetoxy group thus rendering the acetyl group less
susceptible to both nucleophillic deprotection processes. Indeed,
catalytic oxidation with Ley's ruthenium system gave the C13 ketone
that was readily hydrolyzed under basic conditions to provide a
single product, 4, in high yield. Subsequently, we found that this
material could be easily produced from all three of the commonly
available taxoid natural products: taxol, baccatin III, and
10-deacetylbaccatin III. This enone triol 4 gave a convenient
starting point for all of our further studies.
During our preliminary survey of methods for selectively
introducing the C2 benzoyl group, we envisaged the possibility of
directly converting a C1-C2 carbonate into a C2 benzoate by the
simple addition of a nucleophillic phenyl reagent. This method
would provide a double role to the carbonate: first as a convenient
protecting group during a total synthesis of taxol and later as a
direct provider of the crucial benzoate. As shown in Scheme 2, this
method was readily reduced to practice. Treatment of 4 with
phosgene in freshly distilled pyridine provided the desired
carbonate, 5, in good yield. Simple addition of an excess of
phenyllithium to a THF solution of this carbonate at -78 .degree.
C. gave the benzoate as the single product. Acylation under
standard conditions gave the enone 7. We have shown that protection
of the C10 hydroxyl group is unnecessary and that if the C10 acetyl
compound is subjected to this protocol partial deacylation of the
10-position occurs. This result leads us to expect easy access to a
variety of C2 esters, a class of derivatives which was previously
inaccessible and may prove very important given that moietie' s
importance in taxols SAR. A series of these proposed derivatives is
also given in Scheme 2. ##STR2##
Another important step in our total synthesis of taxol is the
introduction of the oxygenation at the C13 position. As shown in
Scheme 3, we employed a two step radical deoxygenation of 2 to give
the C13 deoxy compound 8 as an inseparable mixture of tri- and
tetra-substituted alkenes. Deprotection/reprotection according to
our protocol described above is expected to give rise to the
carbonate 9. This material should be readily converted to 6 by
chromium mediated allylic oxidation. ##STR3##
Conversion of 7 back to taxol proceeded according to literature
precedent. Acylation at the C10 position smoothly gave the expected
enone acetate. Treatment of this material with sodium borohydride
gave, with exclusive regio and stereo chemistry, the correct C13
alcohol. Introduction of the protected side chain, followed by
deprotection should give taxol 1. ##STR4##
Since our synthetic strategy for taxol centers around the reductive
coupling of a dialdehyde to produce the C9-C10 bond, we undertook
studies aimed at oxidatively cleaving this bond. Initial attempts
with lead tetraacetate on both taxol (1) and 10-deacetyl baccatin
III (3) failed to produce cleavage products. As shown in Scheme 5,
the major product in the case of 3 was that of oxidation at the C13
position. Similar studies on the enone 6, failed, with a variety of
reagents, to produce any cleavage products. ##STR5##
Since our synthetic intermediates were not protected in exactly the
same manner as our degradation products, we attempted to protect
both the C1-C2 diol and the C7 hydroxyl group with a variety of
moieties. As shown in Scheme 6, all attempts to introduce acetal or
ketal groups at C1-C2 gave exclusive rearrangement to the cyclic
ether 12. A similar ether has been proposed as the major side
product during attempts to deprotect Baccatin III. As shown in
Scheme 7, attempts to introduce other ethereal protecting groups
than the TES resulted in either no reaction, exclusive
epimerization at the C7 position, or opening of the oxetane via
elimination. ##STR6##
Further details of the invention are provided in Appendex A,
attached.
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